Prodrugs

Initial definition: A pharmacologically inactive chemical entity that when metabolized or chemically transformed by a mammalian system is converted into a pharmacologically active substance Drug Latentiation included later

Process of purposely designing and synthesizing a molecule that specifically requires bioactivation to a pharmacologically active substance

Why use prodrugs? Improve patient acceptability (decrease pain on injection) Alter and improve absorption Alter biodistribution Alter metabolism Alter elimination

Non-Prodrugs

Hard Drugs - compounds that contain structural characteristics required for activity but are not susceptible to metabolism

Increased efficiency by avoiding metabolism No toxic metabolites are formed HOWEVER, less readily eliminated due to lack of metabolism

Soft Drugs - These are the opposite of prodrugs. These compounds are designed and synthesized as ACTIVE compounds that readily undergo metabolic inactivation to nontoxic products

Conversion of Prodrugs

Metabolism (enzyme dependant) Chemical Methods (non-dependant)

Hydrolysis Decarboxylation NOT patient dependant! Stability/Storage issues

Prodrugs

Carrier-linked prodrugs drugs that are attached through a metabolically labile chemical linkage to another molecule designated as the promoiety

The promoiety alters the physical properites of the drug to increase water or fat solubility or provide sitedirected delivery Advantages:

Increased absorption Injection site pain relief Elimination of unpleasant taste Decreased toxicity Decreased metabolic inactivation Increased chemical stability Prolonged or shortened action

Chloramphenicol
Chloramphenicol
OH OH Cl Cl O O-Na+ O O O H N O H O Cl Cl H N O

Esterase

O2N

O2N

or Water
OH O-Na+ O

Chloramphenicol Succinate

Sodium succinate

Enzymatic and intramolecular spontaneous hydrolysis Increased water solubility, ester itself is inactive as an antibiotic Promoiety should be nontoxic and easily excreted Type of promoiety chosen is a function of properties desired

Mutual Prodrug
H3C
O Cl N O HO

OPO3Na2

H3C

OH

Sodium phosphate and Carbon dioxide

Cl

Estermustine Sodium Phosphate Emcyt - Pharmacia & Upjohn

Cl

NH

NH+Cl-

Aziridine
Cl Nornitrogen mustard Cl

Actual alkylating species

Used for metastatic carcinoma of the prostate Promoiety also a drug! Prodrug is selectively taken up into estrogen receptor positive cells then urethane linkage is hydroylzed 17-alphaestradiol slow prostate cell growth Nornitrogen mustard is a weak alkylating agent

Functional Groups in Prodrugs

Carboxylic acids and Alcohols: Most common type of prodrug
O O O
or

Drug

Promoiety

Drug

OH

HO Promoiety

O O Drug

Promoiety

Promoiety

OH

HO Drug

Types of esterase enzymes mediating the hydrolysis process

Ester hydrolase, Lipases, Cholesterol esterases, Acetylcholinesterase, Carboxypeptidase, Cholinesterase Bacterial microflora enzymes Wide number of choices of promoiety alcohols available Steric, electronic and hydrophobicity properties allow rate and extent of hydrolysis to be controlled

Functional Groups in Prodrugs

H3 C CH3 O O H3 C HO HO H3 C CH3 O O O O O NH(CH3)2+-SO4 CH3 Erthromycin estolate Ilosone - Eli Lilly caps,tabs, suspension Antibiotic used to treat upper and lower respiratory infections (URI or LRI), Legionnaire's disease, skin infections

HO

CH3 OMe O H3C CH3 OH

O CH3

CH3

Erythromycin is a very bitter substance easily destroyed at acidic pH

Propionate ester is to increase lipid solubility for improved absorption

Ester must be hydrolyzed for antibacterial activity

Lauryl sulfate salt absorption not affected by food, less bitter after taste and is acid stable

Esters Failure as Prodrugs

R1
O O H N H

S
N

CH3 CH3

CO2R2

R2 = ethyl, propyl, butyl, phenyl Penicillin esters R1

O O
CO2R2

Esterases NO REACTION!

H N

H N

R3

R2 = ethyl, propyl, butyl, phenyl Cephalosporin esters

b-Lactam prodrug Double esters

Why? Increase absorption
H 2N S N
O O

OMe
H N H N
O S

Vantin Pharmacia & Upjohn URI, UTI, Gonorrhea, skin infections

OMe
O CH3 O CH3 O O

Avoid acid catalyzed decomposition

Taking with food

CH3 CH3

Esterase OMe

increases absorption

H 2N S

N
O

H N O

H N
O

HO-Esterase OMe H 2O CO2

O H3C

CH3 O H

CH3 HO CH3

OMe H 2N S Active Drug N

O O
O O

H N

H N

OMe

CH3 O CH3

Other ester prodrugs - soluble

O-Na+

O
Drug
OH

Drug

O O

O O

OH Na+OO O

H+

Sodium succinate prodrug

Sodium succinate

Unstable: use immediately More stable: less prone to hydrolysis by water

Drug
O O O S O-Na+

Sulfatase Drug

OH

HO

O S O-Na+

Sulfate prodrug

Drug

O HO

O P O-Na+

Phosphatase Drug
OH

HO

HO

O P O-Na+

Phosphate prodrug

Amine derivatives as prodrugs

Amides not used due to high stability Most common amine derivative used is a Mannich Base prodrug

H3C HN CH3 N S O O N

CH3 Water CH3 CO2 H

H2 N O

H N O N

CH3 CH3 + CO2 H

O H3C CH3

Hetacillin
N(CH3)2 OH NH2
OH

Ampicillin
Formaldehyde H 2C N
+

Acetone

H 3C

OH

-H2O H

O H

HN Pyrrolidine

Tetracycline

O O H O H OH

O N(CH3)2 OH H N O

Iminium ion

H 3C

Rolitetracycline - A prodrug of N tetracycline with increased water solubility

OH

O O H O H

Mannich Base Chemistry

Mannich Reaction - This is nucleophilic addition reaction of an aldehyde and at least a secondary amine to produce what is known as a schiff base on protonation and elimination of a water molecule. The Schiff base is often stabilized by resonance. The addition of a carbanaion to the schiff base gives another base called the Mannich base. The Mannich base formed can readily eliminate the secondary amine to give the synthetic usefulness of the reaction, but when primary amines or ammonia are used the hydrogen on nitrogen atom can participate in a further reaction to give more complex products.

Azo Prodrugs
Bacterial reductases reductive cleavage Release of 2 amine compounds Occurs in colon discourages small intestine systemic absorption Concentrates the drug at the desired site of action
Sulfapyridine
NHSO2 N

CO2H
NHSO2 N

N N

OH

NH2

Sulfasalazine - Azulfidine - Pharmacia & Upjohn Sulfonamide antibiotic and antiinflammatory Used to treat Ulcerative colitis, rheumatoid arthritis H 2N

+
CO2H OH

5-aminosalicylic acid

Carbonyl prodrugs
Aldehyde and ketone derivatives Little clinical utility with one exception

N Acidic urine pH N N N O 6 H H

4 NH3

Methenamine hippurate Hiprex - Hoechst Marion Roussel Urex - 3M Pharmaceuticals plus a number of combos

Used for prophylaxis or suppression/elimination of frequent UTI

Bioprecursor Prodrugs

Do NOT contain a carrier or promoiety

Contain latent functionality Metabolically or chemically transformed into an active drug Types of activation at are predictable

Oxidative Reductive Phosphorylation

(most common method) (antiviral agents)

Oxidation Example Nabumetone Relafen Smith Kline Beecham

O CH3

Series of oxidative decarboxylation

CH3O

OH O

CH3O

Non-steroidal antiinflammatory Use: Arthritis

Active form of the drug that inhibits Prostaglandin biosynthesis by cyclooxygenase

Bioprecursor Prodrugs
Reduction example - Mitomycin C - Mutamycin - Bristol Myers Adenocarcinoma of the stomach and pancreas
H 2N O
O H 2N H 3C O

H 2N O
OH

H 2N O -OCH3
H2N H3C

O OMe N NH Reduction H2N

H 3C

O OMe N NH

A quinone electron withdrawing

OH A hydroquinone electron donating

N +

NH

-H+ H+

OH H 2N H 3C

DNA
H2N

OH

DNA -CO2 N + NH -NH3

H2N H 3C OH OH

H 2N O O

NH

H3C OH

OH Further alkylation

NH

Electrophile

Bioprecursor Prodrugs
Phosphorylation example
H N O O I H N O I

HO

Viral Thymidine Kinase

O O O P O O O OH

Not lipid soluble

OH Iodoxuridine - Herplex Allergan - lipid soluble! Opthalmic product for Herpes simplex keratitis Higher affininty for viral kinases than mammalian kinases but some toxicity

ATP
H N O I

O O O O -O P O P O P O O O O O OH

TWO mechanisms of action: 1. Inhibits DNA polymerase 2. Incorporated into DNA affording incorrect base pairing and template activity

Chemical Delivery Systems

We have already seen 2 examples of this:

Sulfasalazine an azo compound Methenamine An urinary antibacterial agent

Requirements

Prodrug reach the site of action in high concentrations Knowledge of high metabolism at site Other factors

Extent of organ or site perfusion Information on the rate of prodrug conversion to the active form at both target and non-target sites Rate of input/output of prodrug from the target site

Limit side effects and increase effectiveness

Chemical Delivery Systems

Types

of carriers that have been used

Proteins Polysaccharides Liposomes Emulsions Cellular carriers (erythrocytes and leukocytes) Magnetic control targeting Implanted mechanical pumps
What

is the Basic Goal?

Protect a non-specific biological environment from a drug Protect a drug from a non-specific biological environment Especially evaluated for drugs with a narrow therapeutic window especially anti-cancer agents

Chemical Delivery Systems

The ideal situation:

Prodrug readily transported to the site of action Prodrug is rapidly absorbed at the site Selective and rapid conversion to the active drug Kidney and Liver are easy targets due to high perfusion and high metabolic rates

Other tissue sites can be problematic for the same reasons

Drug migrate slowly (site of action to a site of excretion) Ideal situation is VERY complex to achieve

Example: Methenamine

the lower the pH, the faster the rate of formaldehyde formed blood pH 7.4 therefore, little formaldehyde formed

Chemical Delivery Systems

Example:

Cancer Chemotherapy

Tumor cells have a much higher growth fraction This translates into higher enzymatic activity that can be exploited Target a prodrug to these sites and exploit higher enzyme activity
Example:

L-Dopa or Levodopa Anti-Parkinsonism agent

HO CO2H NH2

Larodopa Roche and Dopar - Procter & Gamble

HO

Decarboxylase
HO

HO

NH2

Dopamine

Brain has a specific transport system for L-amino acids Dopamine does not cross the blood brain barrier efficiently, is rapidly metabolized by oxidative deamination, and can cause peripheral side effects